biostudies-literatureChen XNatural Science Foundation of Zhejiang ProvinceNatural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)National Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)252-257https://www.ebi.ac.uk/biostudies/studies/S-EPMC11840102biostudies-literatureUnknown33(2)Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis European journal of human genetics : EJHGOrigin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus.PMC1184010281571089Y23H090057Zhang FChen JWang BChen MLiu PWang HLin ZYang DHu BShi YWang LFu AXie FWu SLuo WCen ZChen XOuyang ZfalseOrigin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus.Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis 2025-01-01T00:00:00Z2025 Mar2026-07-16T23:11:47.347Z2026-07-12T03:10:58.433ZS-EPMC118401023846773310.1038/s41431-024-01586-y